Antisera raised in different inbred strains of mice to two natural protein antigens under H-2 linked Ir gene control, sperm whale myoglobin and staphylococcal nuclease, have been studied for their specificity for different determinants on the antigen molecule. In the case of nuclease, H-2-linked Ir genes affect the proportion of antibodies to different determinants. The H-2 linkage of this phenomenon has been confirmed of multiple genes in H-2 which have yet to be mapped. In the case of myoglobin, two Ir genes have been mapped to the I-A and I-C subregions of h-2. Recombinant strains with only the gene in L-C (Ir-Mb-2) produce an intermediate level of antibodies to whole myoglobin, lacking antibodies to the C-terminal region (132-153), whereas strains with only the gene Ir-Mb-1 in I-A make antibodies to this region. These results suggest that the responses to different determinants on the same antigen molecule are controlled independently by different genes, and that intermediate responsiveness is only the net effect of high responder genes for some determinants and low responder genes for other determinants.